Project Summary Since its introduction just over a decade ago, functional magnetic resonance imaging (fMRI) has rapidly become an indispensable tool for studies of the working human brain. The vast majority of fMRI studies utilize the blood oxygenation level dependent (BOLD) signal, which reflects the hemodynamic response to neural activity. In these studies, differences in the BOLD signal are typically interpreted as differences in neural activity. However, there is growing evidence that shifts in the baseline vascular state due to factors such as medication, age,and disease can significantly alter the amplitude and shape of the BOLD signal. These factors can increase the variability of the BOLD signal across subjects and experimental conditions and complicate the interpretation of fMRI experiments. The goal of this application is to determine whether non-invasive measures of the baseline vascular state can account for the variability in the BOLD signal that is caused by vasoactive agents and the aging process. The central hypothesis of this proposal, which is supported by strong preliminary data, is that a normalized measure of the power in low frequency components of the BOLD signal, referred to as the 0.1 Hz spectral index, can be used to probe the baseline vascular state and can account for a significant fraction of the variability in the BOLD response. The aims of this proposal are to (1) evaluate the ability of the 0.1 Hz spectral index and other measures of the baseline vascular state to account for the variability in the BOLD response caused by vasoactive agents, and (2) evaluate the ability of these measures to account for age-related variability in the BOLD response. These aims will be achieved using (1) studies that assess the impact of caffeine and hypercapnia on the baseline vascular state and the BOLD response and (2) studies that characterize the baseline vascular state and the BOLD response in young (20 to 45 years old)and old (65 to 95 years old) subjects. Relevance to Public Health The proposed studies are expected to provide the knowledge necessary for the application of the 0.1 Hz spectral index to the improved interpretation of fMRI studies. For example, once the predictive capability of the 0.1 Hz spectral index is demonstrated, it could be applied to studies evaluating the efficacy of various medications for mental illness. By enabling investigators to assess whether medication-related changes in the BOLD response reflect changes in neural activity or are primarily a reflection of the vascular effects of the medication, the 0.1 Hz spectral index would allow investigators to more effectively determine which medications are likely to be of clinical value.